- Email: [email protected]
P.2.c.013 Two generic antidepressant medications and their bio-equivalence or bio-inequivalence
P.2.c Affective disorders and antidepressants - Antidepressants (clinical)
Ip.2.c.0131 Two generic antidepressant medications and their bio-equivalence or bio-inequivalence E Chenu1 " L. Batten1 , G. Zemig2 , E. Ladstaetter2, C. Hebert1 , P. Blier1 . 1 University of Ottawa, IMHR - Mood Disorders Research Unit, Ottawa, Canada; 2Medical University Innsbruck, Experimental Psychiatry Unit Department of General Psychiatry and Social Psychiatry, Innsbruck, Austria Purpose of the study: Generic drugs are lower-cost versions of patent-expired original brand-name medications [1]. According to the regulatory agencies of the European Union, US and Canada, a generic drug must be "identical, or bioequivalent to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use". Bioequivalence is decreed when the ratio of the generic to the reference compound for the area-under-the-curve and maximum plasma concentration (Cmax) fall within a 0.80-1.25 range. A previous report described a high rate of relapse in patients switched from brand to generic formulation of citalopram [2], and similar cases were observed in Canada since the introduction of generic venlafaxine. It was therefore hypothesized that the generic medication was not bio-equivalent to the original one. The aim of the present study was to compare the pharmacokinetic profile of original and generic formulations of citalopram and venlafaxine. Methods: Celexa®/Gen-citalopram® 40mg and Effexor®/ Novo-venlafaxine® (TEVA) XR 75 mg were studied in a randomized cross-over design in healthy volunteers. Plasma levels of drugs were measured at fixed intervals after taking the drugs (citalopram: 1 to 3 hours; venlafaxine: 2 to 6 hours), as well as at steady state (citalopram: day 8; venlafaxine: day 5). The pill/tablet content was also evaluated. Results: (i) Citalopram: the plasma levels of citalopram were similar after ingestion of the brand and generic drugs (Cmax: 27±2 and 28±3 nglmL for the brand and the generic formulations, respectively). The corresponding ratio of the log-transformed values of Cmax was of 99%. No differences were obtained at steady state. (ii) Venlafaxine: after ingestion of venlafaxine, the Cmax were 36±6 and 52±8 nglmL in the brand and generic groups, respectively (p < 0.001). The ratio of the log-transformed values of Cmax was of 150%, and therefore not within the acceptable 80% to 125% range. The concentration of the active metabolite of venlafaxine (O-Desmethyl-Venlafaxine, ODV) was also significantly increased in the generic group (-+43 to -+48%; P < 0.05 at time 3, 4, 5 and 6 hours). No differences were obtained at steady state for both ODV and venlafaxine. The number of side effects reported by the participants was significantly higher under generic medication (14) than under brand-name medications (4; p < 0.05). Pill contents were identical in the two groups, but extraction of generic venlafaxine occurred more readily than the brand which required an additional sonication. Conclusion: Gen-citalopram® 40mg appeared to be bioequivalent to Celexa® 40 mg, whereas Novo-venlafaxine® XR 75 mg was not bioequivalent to Effexor® XR 75 mg. The Novo-venlafaxine® formulation was releasing its active ingredient more rapidly than the Effexor and outside of the prescribed norm, resulting in higher plasma levels and more side effects. Further studies are necessary to evaluate the clinical impact of switching from one formulation to the other in depressed patients. Source of funding for this work: unrestricted grants from Astra Zeneca, Biovail, Organon, and Wyeth Pharmaceuticals. Dr Blier has received honoraria for consultancy with Lundbeck and Wyeth
S411
Pharmaceuticals, for speaking engagements, and has produced under contract educational material for these companies. References [I] Borgheini, G., 2003 The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther 25, 15781592 [2] Van Ameringen, M., Mancini, C., Patterson, B., Bennett, M., 2007 Symptom relapse following switch from Celexa to generic citalopram: an anxiety disorders case series. J Psychopharmacol 21, 472--476
1P.2.c.0141 Duloxetine in the treatment of depression comorbid with anxiety: a pilot study with 12-month outcomes R. Bassetti 1 " M.E Bosi2 , A. Colomb03 , A. Roar0 3 , R. Truzoli2 , G. Ba2 . 1L.Sacco Hospital, Mood Disorder Unit Department of Psychiatry Universiy of Milan, Milan, Italy; 2L.Sacco Hospital, Mood Disorder Unit Department of Psychiatry University of Milan, Milan, Italy; 3L.Sacco Hospital, Mood Disorder Unit Department ofPsychiatry University ofMilan, Milan, Italy Background: Depression and anxiety are both common psychiatric conditions. In clinical practice, comorbidity between anxiety and depressive disorders represents the norm rather than the exception: 50% of depressed patients suffer also from an anxiety disorder, both in syndromic and in "subthreshold" forms [1]. The interface of anxiety and depression affects the course and treatment of both the conditions. Anxiety symptoms may appear as prodromes of a depressive episode and affect significantly the patient's functioning, illness severity with more frequent chronic outcome, higher suicidal risk, alcohol and drug abuse, recurrence and relapse rates and persistence of residual depressive or anxiety symptoms. Thus, a correct clinical diagnosis of comorbidity and a targeted treatment with an efficacy both on anxiety and depressive clusters symptoms are crucial for the patient's outcome. Dual action antidepressant duloxetine, through its effect on serotonin and norepinephrine modulation, appeared to show these peculiarities in short and medium-treatment studies [2,3]. Aim of the study: To evaluate the efficacy of duloxetine in the long- term treatment of depression with or without comorbidity with anxiety disorders. Methods: Fourteen outpatients with Major Depressive Episode (MDE) and comorbid or not Anxiety Disorders (Generalized Anxiety Disorder, Panic Disorder, Obsessive-Compulsive Disorder, Social and Specific Phobia and Anxiety Disorder NOS), diagnosed according to DSM-IV-TR criteria through a semi-structured interview, were recruited from the Mood Disorder Unit of L. Sacco Hospital. All patients gave their informed consent to participate into the study and were treated, according to an open-label design, with Duloxetine from 60 mg to 120 mg day, according to clinical judgment, for a 12-month period. Statistical analysis was performed with non parametric tests on the sample subdivided in two groups according to the presence (n = 5) or not (n = 9) of comorbid anxiety disorders. The main clinical and demographic variables were analysed and compared at baseline. To evaluate the treatment response in the two groups, patients were assessed with Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D) and Montgomery Asberg Rating Scale (MADRS) at baseline, one, six, and twelve months. Results: All patients at 12-month treatment assessment showed a significant decrease ofHAM-D (p = 0.0001), HAM-A (p=0.001)
Ip.2.c.0131 Two generic antidepressant medications and their bio-equivalence or bio-inequivalence E Chenu1 " L. Batten1 , G. Zemig2 , E. Ladstaetter2, C. Hebert1 , P. Blier1 . 1 University of Ottawa, IMHR - Mood Disorders Research Unit, Ottawa, Canada; 2Medical University Innsbruck, Experimental Psychiatry Unit Department of General Psychiatry and Social Psychiatry, Innsbruck, Austria Purpose of the study: Generic drugs are lower-cost versions of patent-expired original brand-name medications [1]. According to the regulatory agencies of the European Union, US and Canada, a generic drug must be "identical, or bioequivalent to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use". Bioequivalence is decreed when the ratio of the generic to the reference compound for the area-under-the-curve and maximum plasma concentration (Cmax) fall within a 0.80-1.25 range. A previous report described a high rate of relapse in patients switched from brand to generic formulation of citalopram [2], and similar cases were observed in Canada since the introduction of generic venlafaxine. It was therefore hypothesized that the generic medication was not bio-equivalent to the original one. The aim of the present study was to compare the pharmacokinetic profile of original and generic formulations of citalopram and venlafaxine. Methods: Celexa®/Gen-citalopram® 40mg and Effexor®/ Novo-venlafaxine® (TEVA) XR 75 mg were studied in a randomized cross-over design in healthy volunteers. Plasma levels of drugs were measured at fixed intervals after taking the drugs (citalopram: 1 to 3 hours; venlafaxine: 2 to 6 hours), as well as at steady state (citalopram: day 8; venlafaxine: day 5). The pill/tablet content was also evaluated. Results: (i) Citalopram: the plasma levels of citalopram were similar after ingestion of the brand and generic drugs (Cmax: 27±2 and 28±3 nglmL for the brand and the generic formulations, respectively). The corresponding ratio of the log-transformed values of Cmax was of 99%. No differences were obtained at steady state. (ii) Venlafaxine: after ingestion of venlafaxine, the Cmax were 36±6 and 52±8 nglmL in the brand and generic groups, respectively (p < 0.001). The ratio of the log-transformed values of Cmax was of 150%, and therefore not within the acceptable 80% to 125% range. The concentration of the active metabolite of venlafaxine (O-Desmethyl-Venlafaxine, ODV) was also significantly increased in the generic group (-+43 to -+48%; P < 0.05 at time 3, 4, 5 and 6 hours). No differences were obtained at steady state for both ODV and venlafaxine. The number of side effects reported by the participants was significantly higher under generic medication (14) than under brand-name medications (4; p < 0.05). Pill contents were identical in the two groups, but extraction of generic venlafaxine occurred more readily than the brand which required an additional sonication. Conclusion: Gen-citalopram® 40mg appeared to be bioequivalent to Celexa® 40 mg, whereas Novo-venlafaxine® XR 75 mg was not bioequivalent to Effexor® XR 75 mg. The Novo-venlafaxine® formulation was releasing its active ingredient more rapidly than the Effexor and outside of the prescribed norm, resulting in higher plasma levels and more side effects. Further studies are necessary to evaluate the clinical impact of switching from one formulation to the other in depressed patients. Source of funding for this work: unrestricted grants from Astra Zeneca, Biovail, Organon, and Wyeth Pharmaceuticals. Dr Blier has received honoraria for consultancy with Lundbeck and Wyeth
S411
Pharmaceuticals, for speaking engagements, and has produced under contract educational material for these companies. References [I] Borgheini, G., 2003 The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther 25, 15781592 [2] Van Ameringen, M., Mancini, C., Patterson, B., Bennett, M., 2007 Symptom relapse following switch from Celexa to generic citalopram: an anxiety disorders case series. J Psychopharmacol 21, 472--476
1P.2.c.0141 Duloxetine in the treatment of depression comorbid with anxiety: a pilot study with 12-month outcomes R. Bassetti 1 " M.E Bosi2 , A. Colomb03 , A. Roar0 3 , R. Truzoli2 , G. Ba2 . 1L.Sacco Hospital, Mood Disorder Unit Department of Psychiatry Universiy of Milan, Milan, Italy; 2L.Sacco Hospital, Mood Disorder Unit Department of Psychiatry University of Milan, Milan, Italy; 3L.Sacco Hospital, Mood Disorder Unit Department ofPsychiatry University ofMilan, Milan, Italy Background: Depression and anxiety are both common psychiatric conditions. In clinical practice, comorbidity between anxiety and depressive disorders represents the norm rather than the exception: 50% of depressed patients suffer also from an anxiety disorder, both in syndromic and in "subthreshold" forms [1]. The interface of anxiety and depression affects the course and treatment of both the conditions. Anxiety symptoms may appear as prodromes of a depressive episode and affect significantly the patient's functioning, illness severity with more frequent chronic outcome, higher suicidal risk, alcohol and drug abuse, recurrence and relapse rates and persistence of residual depressive or anxiety symptoms. Thus, a correct clinical diagnosis of comorbidity and a targeted treatment with an efficacy both on anxiety and depressive clusters symptoms are crucial for the patient's outcome. Dual action antidepressant duloxetine, through its effect on serotonin and norepinephrine modulation, appeared to show these peculiarities in short and medium-treatment studies [2,3]. Aim of the study: To evaluate the efficacy of duloxetine in the long- term treatment of depression with or without comorbidity with anxiety disorders. Methods: Fourteen outpatients with Major Depressive Episode (MDE) and comorbid or not Anxiety Disorders (Generalized Anxiety Disorder, Panic Disorder, Obsessive-Compulsive Disorder, Social and Specific Phobia and Anxiety Disorder NOS), diagnosed according to DSM-IV-TR criteria through a semi-structured interview, were recruited from the Mood Disorder Unit of L. Sacco Hospital. All patients gave their informed consent to participate into the study and were treated, according to an open-label design, with Duloxetine from 60 mg to 120 mg day, according to clinical judgment, for a 12-month period. Statistical analysis was performed with non parametric tests on the sample subdivided in two groups according to the presence (n = 5) or not (n = 9) of comorbid anxiety disorders. The main clinical and demographic variables were analysed and compared at baseline. To evaluate the treatment response in the two groups, patients were assessed with Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D) and Montgomery Asberg Rating Scale (MADRS) at baseline, one, six, and twelve months. Results: All patients at 12-month treatment assessment showed a significant decrease ofHAM-D (p = 0.0001), HAM-A (p=0.001)